Osmotic pump controlled release preparations are typical representatives of sunstained and controlled release preparations, characterized in that they use osmotic pressure as the driving force for drug release and follow the zero-order release kinetics. Osmotic pump controlled release preparations have become a hot topic of research and development all over the world. Among them, osmotic pump controlled release tablet is the most common dosage form of oral osmotic pump controlled release preparations.
Based on the structural characteristics, oral osmotic pump preparations can be divided into two types: mono-compartment osmotic pumps and multi-compartment osmotic pumps. The mono-compartment osmotic pumps are generally used for water-soluble drugs, and consist of a tablet core and a coating film. The tablet core consists of a drug and a high-permeability material. The coating film is commonly a rigid semipermeable membrane formed by a polymer material such as cellulose acetate or ethyl cellulose, and one or more releasing orifice(s) are usually drilled by laser or other means (such as mechanical force) on the semipermeable membrane and used as the output channel of drugs. When being used, the high-permeability material in the tablet core produces high osmotic pressure after being dissolved, then a static pressure difference between inside and outside of the semipermeable membrane is formed. Thus, under this pressure difference, a drug suspension or solution outflows from the tablet, while external water inflows into the tablet, moreover, the inflowing speed of water is equal to the outflowing speed of the drug suspension or solution. Mono-compartment osmotic pump controlled release tablets are mainly suitable for water-soluble drugs, and not applicable to water-insoluble drugs, especially poorly water-insoluble drugs. In addition, due to the limitation of structure, mono-compartment osmotic pumps will no longer release drugs at a constant rate at the late stage of release, and the osmotic pressures are reduced and may even cause drug residue in preparations, like ordinary sustained-release formulations. Due to the above-mentioned problems present in mono-compartment osmotic pumps, multi-compartment osmotic pumps have subsequently been developed.
Multi-compartment osmotic pumps consist of at least two layers: a drug-containing layer and a push layer, which constitute a drug compartment and a force compartment respectively. The most widely used osmotic pumps are double-compartment osmotic pumps. The drug-containing layer consists of a drug, a penetration-promoting agent and a suspending agent. The push layer consists of one or more swellable polymer materials and a penetration-promoting agent. When being used, water enters into the tablet core through the semipermeable membrane, resulting in the drug-containing layer is softened by absorbing water, meanwhile, the polymer material in the push layer swells by absorbing water and squeeze the drug compartment, so that drugs are released from the releasing orifices. A constant osmotic pressure will keep a constant speed of water entering into the tablet core, thereby keep a constant swelling speed of the polymer material by absorbing water in order to maintain the persistence of a constant osmotic pressure and achieve a constant drug release rate. In addition, the drug, whether existing in a solution or a suspension, can be squeezed out of the semipermeable membrane by the swelled push layer. However, mono-compartment osmotic pump controlled release tablets will cause the penetration-promoting agent and the drug being separated from each other during the delivery of poorly water-soluble drugs, thereby resulting in drug residue in the tablet core. Thus, multi-compartment osmotic pumps are applicable to all types of drugs, and they have more obvious advantages in the aspect of deliverying poorly water-soluble drugs compared with mono-compartment osmotic pump controlled release tablets. At present, successful osmotic pump preparations on the market are mostly double-compartment osmotic pump tablets. Successful examples include Nifedipine double-compartment osmotic pump tablets (Adalat®) developed by Bayer Company of Germany and Verapamil hydrochloride controlled release tablets designed and developed by Alza company of the United States based on the Nifedipine double-compartment osmotic pump tablets. At present, the technique of double-compartment osmotic pump preparations is the most mature and appropriate method for industrial method for preparing poorly water-insoluble drugs into osmotic pump preparations. Multiple-compartment (more than two compartments) osmotic pump controlled release tablets, for example, three-compartment osmotic pump controlled release tablets, are seldom used since their preparation processes are very onerous and they do not have apparent advantages in performance over double-compartment osmotic pumps. The important osmotic pump controlled release tablets on the market in the foreign countries are shown in Table 1.
TABLE 1important osmotic pump controlled release tablets on the market in foreign countriesThe materialof semi-active permeabledeveloped No.Trade nameingredient membraneby1AcutrimPhenylpropanol-CAAlzaamine2Alpress LPPrazosinCAAlza3Cardura XLDoxazosin CAAlzaMesylate4Covera HSVerapamilCAAlza5ConcentaMethylphenidateCAAlza6Ditropphan XL Oxybutynin CAAlzaChloride7DynaCirc CRIsradipineCAAlza8Efidac 24Norpseudo- CAAlzaPseudoephedrineephedrine9Efidac 24ChlorpheniramineCAAlzachlorpheniramine10Efidac 24BrompheniramineCAAlzaBrompheniramine&and Norpseudo-Pseudoephedrineephedrine11Glucotrol XLGlipizideCAAlza12Procardia XLNifedipineCAAlza13TeczemEnalapril andCAMerck&DiltiazemHoechst Marion14TiamateDiltiazemCAMerck15VolmaxSalbutamolCAAlza
Semipermeable membrane is very important for the control of drug release in oral osmotic pump formulations. It must meet the following requirments: (1) sufficient wet strength; (2) water can penetrate through it selectively, but solute can not penetrate through it; (3) biocompatible. Ideal semipermeable membrane should possesses the following characteristics:    (1) selective permeability: water can effectively enter the inside of the tablet core, and the permeation-active substances and drug inside of the tablet core can be effectively prevented from being released by diffusion through the semipermeable membrane;    (2) high strength and rigidity: it has a certain strength to prevent the membrane from breaking due to the internal static pressure difference or expansion of the tablet core so that the release behavior suddenly changes. If the semipermeable membrane has a certain tensile strength, the extrusion force produced by expansion of the push layer will be counteracted to some extent, so that the suddenly change of release behavior will be avoided;    (3) without aging: the semipermeable membrane does not age (i.e., components in the semipermeable membrane integrate with each other more and more closely) during storage, so that the permeability will not change and the stabilities of the samples will not reduce during storage; and    (4) the semipermeable membrane must be transparent or translucent, thereby making it easy to identify the drug-containing layer (drug compartment) and the push layer (force compartment) when orifices are drilled by laser.
Cellulose acetate (CA) is most commonly used as a semipermeable membrane material. Other materials such as ethyl cellulose (EC) is also mentioned in literatures to be used as a film-coating of osmotic pumps. However, ethyl cellulose has poor water permeability, so it has not been used in the production of osmotic pump controlled release tablets (S. Rose and J. F. Nelson, Aust. J. Exp. Biol. Med. Sci., 1995, 33,415.). It can also be seen from Table 1, CA is used as a semipermeable membrane material in various important osmotic pump controlled release tablets on the market.
The semipermeable membrane made of different coating materials has different water permeability, which is related to the membrane penetration coefficient (k). The semipermeable membrane material now used is commonly cellulose acetate (CA), to which plasticizer is usually added to adjust the penetration rate thereof. Hydrophilic plasticizer polyethylene glycol (PEG) can increase the drug release rate, while hydrophobic plasticizer glycerol triacetate has an opposite effect.
For example, the semipermeable membrane of Procardia XL (Adalat®, nifedipine controlled release tablet) on the market was measured by differential scanning calorimetry (DSC) and compared with a single cellulose acetate membrane and a single PEG at the same time. It was found based on the melting endothermic peak that the combination of CA and PEG6000 was effected in the semipermeable membrane of Adalat to control drug release, wherein PEG plays a dual role as a plasticizer and a pore-forming agent.
We found that osmotic pump controlled release tablets prepared using common semipermeable membrane material at present (for example, cellulose acetate/polyethylene glycol) have a good release profile at a period of time after preparation, however, after being stored for a period of time, the release properties began to deteriorate. The longer the product is stored, the more obviously the release properties deteriorate. The release often reduces remarkably at the latter half of the validity period prescribed (usually two years or so), and even the drug can not be released at all after 2 years since production at factory. The reason is that PEG might plays two opposing roles of a plasticizer and a pore-forming agent at the same time, so hidden troubles are present for the storage stability of osmotic pump tablets. Since PEG has a plasticizing effect, it will combine with cellulose acetate constantly during the storage, thereby reducing the dissolution ratio in the release process. Reduced pore-forming effect results in decreased membrane permeability, so that the release becomes slow, popularly called physical aging. PEG with low molecular weight, due to its low melting point, the thermal stability thereof is even worse. Using diethyl phthalate as a plasticizer has the same problem. In order to overcome the release decline caused by physical aging, excessive feeding (namely, active ingredient of an amount of more than that calculated by the labelled amount is added during the preparation) is often required, in order to ensure the release in conformity of the requirement within the validity period.
For example, we found that when the influencing factors were examined by storing commercially available Glipizide controlled release tablets under the conditions of 40° C., 60° C., RH 75% and RH 92.5%, the results showed that the release were significantly decreased. In the membrane weight loss experiments, we found that the weight loss of membrane under each condition was significantly decreased relative to day 0 compared with samples that were not subjected to accelerated testing under the above conditions, suggesting that the membrane permeability was lowered, namely, in the above storage conditions, varying degrees of aging occurred in the semipermeable membrane.
Ethyl cellulose is a hydrophobic polymer material, which is widely used in sustained-release pellets. It is well known that the particle size of sustained-release pellets is generally in the range of 0.5-2 mm, so such a small particle size will inevitably lead to a very large surface area of release for a certain amount of products. Thus, for a water-soluble drug, a membrane with relatively smaller permeability has to be used to prepare a sustained-release preparation. Ethyl cellulose has a unique advantage in the field of sustained-release pellets due to its characteristics of small permeability, good film-forming property, and facilitating regulation of the release, and it can effectively control the drug release in the cases of small weight increase of coating. The active ingredient in sustained-release pellets mainly release in a dissolution-diffusion mode, which is suitable for water-soluble drugs. Generally, the release rate is decreased with the decline of drug concentration, and the entire release process is a first-order kinetics process or a fake first-order kinetics process. However, for water-insoluble drugs, it is difficult for drug to release in a dissolution-diffusion mode. If ethyl cellulose is selected as the membrane material, complex solubilization technology has to be used. Thus, the difficulty of the process is increased, and the reproducibility becomes poor. As a result, a large amount of drug will often be residued in the sustained-release pellets or released in an irregular manner.
The application of ethyl cellulose in the semipermeable membrane of osmotic pumps is limited due to its poor permeability. Thus, despite ethyl cellulose could be used as the semipermeable membrane material of osmotic pumps as mentioned in general literatures, ethyl cellulose has not been used in the osmotic pump preparations on the market. Furthermore, it has not been reported in the literatures that ethyl cellulose could be successfully used in the preparations of osmotic pump and thereby achieving good effects.
In addition to aging of the semipermeable membranes mentioned above, the present inventor also found by research that the structures of the existing osmotic pump tablets are also often important reasons causing drug residues, especially for double-compartment or multi-compartment osmotic pump tablets. Taking double-compartment osmotic pump tablets as an example, the double-compartment osmotic pump tablets in the prior art usually belong to symmetric double-compartment osmotic pump tablets with small curvature, i.e., both sides of the tablets are symmetric or substantively symmetric. The angle θ1 and θ2 formed between the outer curved surface (the upper and lower surface in FIG. 1) of the drug-containing layer and the lateral surface are equal or substantially equal and are both small (generally less than 120°), and the ratio L1/r (L1 is the vertical distance from the central vertex of the outer curved surface (or called “the upper surface”) of the drug-containing layer of the tablet core to the plane formed by the intersection line between the upper surface and the lateral surface (FIG. 1), r is the radius of the tablet core (FIG. 1)) is also small (generally less than 0.27) (see FIG. 1). Such a structure results in a corner pocket in the push layer, that is to say, due to the small angle between the outer curved surface of the drug-containing layer and the lateral surface, it is difficult for the drug-containing layer on the edge of the tablet core to be squeezed by the push layer and thus can not move smoothly to the releasing orifices, thereby the push layer is expanded towards the center of the tablet core, so the drug at the edge far away from the central releasing orifices in the drug-containing layer of the tablets can not be easily pushed out. Moreover, the ratio L1/r (L1 is the vertical distance from the central vertex of the upper surface to the plane formed by the intersection line between the upper surface and the lateral surface, and r is the radius of the tablet core) is smaller, thus the push layer tends to pass through the drug-containing layer and extruded from the releasing orifices. The drug-containing layer residued in the semipermeable membrane cannot be released sustainedly, resulting in a large amount of drug left in the drug-containing layer.
It should be noted that, for the osmotic pump tablets whose outer curved surface of the drug-containing layer belongs to a part of the regular spherical surface, the changes of the above two factors, i.e., (1) the angle θ1 formed between the outer curved surface of the drug-containing layer (the upper surface in FIG. 1) and the lateral surface, and (2) the ratio L1/r (L1 is the vertical distance from the central vertex of the outer curved surface (the upper surface in FIG. 1) to the plane formed by the intersection line between the outer curved surface of the drug-containing layer and the lateral surface (FIG. 1), and r is the radius of the tablet core (FIG. 1)) are consistent, that is to say, the angle θ1 and the ratio L1/r is similarly increased or decreased. However, for the osmotic pump tablets whose outer curved surface of the drug-containing layer belongs to a part of approximate spherical or ellipsoidal surface, the effects of the above two factors (1) and (2) may not be consistent or to the same extent. In other words, factor (1), i.e., the value of angle θ1 has more impact on the drug release at the edge far away from the central release orifice, however, factor (2), i.e., the ratio L1/r has a greater impact on the push layer whether could pass through the drug-containing layer and be squeezed out from the releasing orifices.